Sarcoidosis of the lung is primarily an interstitial lung disease in which the inflammatory process involves the alveoli, small bronchi, and small blood vessels. These individuals typically have dyspnea, particularly with exercise and dry cough. Hemoptysis is rare, as is production of sputum.
As sarcoidosis progresses, small lumps, or granulomas, appear in the affected tissues. In the few cases where the granulomas do not heal and disappear, the tissues tend to remain inflamed and become scarred (fibrotic).
From 20 to 30 percent of sarcoidosis patients are left with permanent lung damage. In 10 to 15 percent of the patients, sarcoidosis can become chronic.
Symptoms of sarcoidosis may be caused by a number of factors, including the “mass effect” of the granuloma(s); immune complex vasculitis (as occurs in erythema nodosum); metabolically active granulomas; and fibrotic distortion lasting even after resolution of the granulomatous lesions.
The lungs are the primary target of this disease. About 88 percent of patients with sarcoidosis have lung involvement. It is customary to stage intrathoracic sarcoidosis by comparing current chest radiographs with the chest radiograph taken on initial presentation. Intrathoracic sarcoidosis is divided into four stages. Approximately 8 percent of patients with sarcoidosis present at stage zero. During this stage, the chest radiograph is normal in the presence of multisystem involvement. Results of pulmonary function testing are usually normal, and most patients remit spontaneously. About 51 percent of patients (including the patient described in the illustrative case) present at stage 1. During this stage, chest radiographs show bilateral hilar lymphadenopathy with or without enlarged right paratracheal nodes.
Results of pulmonary function tests are usually normal except for a decreased diffusing capacity, but mechanics are normal. Most patients are asymptomatic or have nonpulmonary symptoms. Most patients (70 to 75 percent) remit within two years, and only 10 to 15 percent progress to stage 2.
Twenty-nine percent of patients with sarcoidosis present at stage 2. During this stage, chest radiographs show hilar lymphadenopathy associated with diffuse pulmonary infiltration. The signs and symptoms are usually mild in relation to the severity of the abnormalities shown on radiograph. Multiple pulmonary nodules or infiltrates may also be present. Results of pulmonary function testing demonstrate restrictive disease with a decreased diffusing capacity, although obstructive changes resulting from bronchial involvement may also be present. One half of these patients undergo spontaneous remission, but 25 to 30 percent remain at stage 2 or progress to stage 3. In patients with stage 3 sarcoidosis, the chest radiograph shows diffuse pulmonary infiltration without hilar lymphadenopathy.
Only about 12 percent of patients present at stage 3. The chest radiograph frequently shows fibrosis with small lung volumes, elevation of the diaphragms and “honeycombing” (fine fibrosis occurring throughout the interstitial lung tissue).
The patient presenting with stage 3 sarcoidosis may have minimal symptoms, (i.e., cough, dyspnea, mild weight loss) or significant problems, including pulmonary hypertension, cor pulmonale and respiratory failure. Many patients in stage 3 have intrinsic restrictive changes on pulmonary function testing but, as a result of bronchial involvement, many also have obstructive changes. Patients at stage 3 usually undergo a chronic course; complications such as pulmonary fibrosis are common and irreversible. Also, at this stage, extrapulmonary findings are more common, especially skin involvement.6 In up to 30 percent of patients at stage 3, sarcoidosis spontaneously remits within two years.
Table 1 shows the stages of sarcoidosis and the radiographic findings at the time of diagnosis. Other intrathoracic radiographic findings seen in patients with sarcoidosis include alveolar infiltrates that may appear extensive or patchy, atelectasis, nodular cavitation, pleural thickening, pleural effusions and calcifications.
TABLE 1Stages of SarcoidosisStagePatients presenting at this stage (%)Findings on chest radiographResults of pulmonary function testingSigns and symptomsPatients expected to go into remission (%)08 to 10Normal (but with multisystem involvement)NormalVaries with system affectedMost remit spontaneously151Bilateral hilar lymphadenopathy with or without enlarged rightparatracheal nodesNormal, except for decreased diffusing capacity; normal mechanicsMost asymptomatic or with nonpulmonary complaints70 to 75% remit within two years; 10 to 15% progress to stage 2229Hilar lymphadenopathy with diffuse pulmonary infiltration; pulmonarynodules may be seenUsually restrictive changes with decreased diffusing capacity; obstructivechanges may bepresentUsually mild in relation to the severity of the radiographic findings50% spontaneously remit; 25 to 30% persist at stage 2 or progress tostage 3312Diffuse pulmonary infiltration, but without hilar lymphadenopathy;fibrosis; small lung volumes; elevated diaphragms; effusions;calcifications; “honeycombing”Primarily restrictive changes, but with obstructive changes due tobronchial involvement; changes may be severeVaries: may be minimal (cough, dyspnea, weight loss) to severe (corpulmonale, pulmonary hypertension; may progress to respiratory failure)30% spontaneously remit within two yearsInformation from reference. Chesnutt AN. Enigmas in sarcoidosis. West J Med 1995; 162: 519-26.
The goals of treatment for sarcoidosis include resolving inflammatory lesions that are interfering with organ function, preventing pulmonary fibrosis and diminishing symptoms. If the patient presents with stage 1 or stage 2 disease with normal pulmonary function tests and no life-threatening signs or symptoms, observation is all that is necessary, as sarcoidosis is usually a self-limited disease and does not require specific therapy. Treatment is indicated if the patient has systemic symptoms or if deterioration in lung function is present at any stage, or if the patient presents with or progresses to stage 3 disease.
Corticosteroids continue to be the mainstay of therapy, although they have not been proved to prolong life. Several different protocols exist. To induce disease regression, treatment with prednisone may be started at a dosage of 40 to 60 mg per day given in divided doses for six to eight weeks, then tapered to a dosage of 15 to 20 mg per day over four to six months. A dosage of 40 to 60 mg of prednisone every other day has also been used for initial treatment, with excellent results.3,8 
A patient may then be maintained on a dosage of 5 to 10 mg per day to suppress disease activity for up to one year. Patients should receive treatment if they have the following forms of sarcoidosis: hypercalcemia and hypercalciuria, disfiguring skin lesions, ocular sarcoidosis (this should be treated with topical and/or systemic steroids), cardiac sarcoidosis, neurologic sarcoidosis and other organ involvement that is determined to be clinically severe.8 Relapse occurs in 25 to 40 percent of patients with sarcoidosis within two to three months after discontinuing corticosteroid therapy. If this occurs, clinical examination and laboratory testing should be repeated. Some experts utilize “pulse therapy” with intravenous methylprednisolone at a dosage of 3 g per day for three days during acute exacerbations.3 Inhaled steroids have been used in patients with sarcoidosis for relief of symptoms, but it has not been proved that this therapy reduces disease progression. Inhaled and oral bronchodilators, supplemental oxygen and synthetic “liquid” tears have also been used to reduce symptoms. Topical ophthalmic steroids have been used to reduce ocular manifestations of sarcoidosis. If symptoms of erythema nodosum and arthritis are present in patients with stage 2 disease, a nonsteroidal anti-inflammatory drug such as indomethacin (Indocin), in a dosage of 25 mg three times daily, may be used.8 
Newer therapies have been reported. Hydroxychloroquine (Plaquenil), given in a dosage of 200 mg every other day for nine months, may be useful in the treatment of cutaneous sarcoidosis but can permanently damage the eyes; consequently, ocular examinations must be performed frequently. Hydroxychloroquine has also been found to be helpful in the management of hypercalcemia.1 Methotrexate (Rheumatrex), in a low dosage of 7.5 to 15 mg once per week, has been shown to be of benefit in the treatment of refractory sarcoidosis, especially musculoskeletal and cutaneous forms.1 Other treatments are available, but few controlled trials have been performed: chlorambucil (Leukeran), cyclophosphamide (Cytoxan) and azathioprine (Imuran). Rarely, lung transplantation has been performed in patients with severe, refractory disease, with varying results. Several patients had a recurrence of granulomatous disease in the transplanted lung.2,10 
Vasoactive Intestinal Peptide (VIP):
VIP is a 28 amino acid peptide consisting of the following amino acid sequence (from N- to C-terminal):
(SEQ ID No. 1)His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg- Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn- Ser-Ile-Leu-Asn.
Healthy individuals exhibit low concentration of VIP (<40 pg/ml serum).
VIP is a widely distributed peptide hormone which mediates a variety of physiological responses including gastrointestinal secretion, relaxation of gastrointestinal vascular and respiratory smooth muscle, lipolysis in adipocytes, pituitary hormone secretion, and excitation and hyperthermia after injection into the central nervous system. Under physiologic conditions VIP acts as a neuroendocrine mediator. Some recent findings suggest that VIP also regulates growth and proliferation of normal as well as malignant cells (Hultgardh, Nilsson A., Nilsson, J., Jonzon, B. et al. Growth-inhibitory properties of vasoactive intestinal polypeptide. Regul. Pept. 22, 267-274. 1988). The biological effects are mediated via specific receptors (VIP-R) located on the surface membrane of various cells (Ishihara, T., Shigemoto, R., Mori, K. et al. Functional expression and tissue distribution of a novel receptor for vasoactive intestinal polypeptide. Neuron 8, 811-819. 1992). VIP may exert stimulating and trophic effects on neoplastic cells from neuroblastoma, breast, lung and colon cancer (e.g. Moody et al., Proc. Natl. Acad. Sci. USA, 90, 4345, 1993), inducing its own receptors by feedback mechanisms. In some cases VIP produced dose-dependent stimulation of mitosis (Wollman et al., Brain Res., 624, 339, 1993). VIP and biologically functional analogues and derivatives thereof are shown to have vascular smooth muscle relaxant activity (Maruno, K, Absood, A., and Said, S. I. VIP inhibits basal and histamine-stimulated proliferation of human airway smooth muscle cells. Am. J. Physiol. 268, L1047-L1051, 1995), hair growth activity, apoptosis activity enhanced sustained bronchodilation activity without remarkable cardiovascular side effects, and are effective at disorders or diseases relating to bronchial spasms including asthma, some cases of hypertension, impotence, ischaemia, dry eye and mental disorders, such as Alzheimer's disease (see e.g. WO 9106565, EP 0536741, U.S. Pat. No. 3,880,826, EP 0204447, EP 0405242, WO 9527496, EP 0463450, EP 0613904, EP 0663406, WO 9735561, EP 0620008).
VIP receptor has been detected on airway epithelium of the trachea and the bronchioles. It is also expressed in macrophages surrounding capillaries, in connective tissue of trachea and bronchi, in alveolar walls, and in the subintima of pulmonary veins and pulmonary arteries. Pepidergic nerve fibers are considered the source of VIP in the lungs (e.g.: Dey, R. D., Shannon-W A, Jr, and Said, S. I. Localization of VIP-immunoreactive nerves in airways and pulmonary vessels of dogs, cat, and human subjects. Cell and Tissue Research 220, 231-238. 1981; Said, S. I. Vasoactive intestinal polypeptide (VIP) in asthma. Ann. N.Y. Acad. Sci. 629, 305-318. 1991). VIP decreases the resistance in the pulmonary vascular system (e.g.: Hamasaki, Y., Mojarad, M., and Said, S. I. Relaxant action of VIP on cat pulmonary artery: comparison with acetylcholine, isoproterenol, and PGE1. J. Appl. Physiol. 54, 1607-1611. 1983; Iwabuchi, S., Ono, S., Tanita, T. et al. Vasoactive intestinal peptide causes nitric oxide-dependent pulmonary vasodilation in isolated rat lung. Respiration 64, 54-58. 1997; Saga, T. and Said, S. I. Vasoactive intestinal peptide relaxes isolated strips of human bronchus, pulmonary artery, and lung parenchyma. Trans. Assoc. Am. Physicians. 97, 304-310.1984). Further studies show a high rate of VIP-R expression in the lung which is reflected in a high uptake of radiolabeled VIP in the lung of PPH patients who were injected 99mTc-VIP (e.g.: Raderer, M., Kurtaran, A., Hejna, M. et al. 123I-labelled vasoactive intestinal peptide receptor scintigraphy in patients with colorectal cancer. Br. J. Cancer 78, 1-5. 1998; Raderer, M, Kurtaran, A., Yang, Q. et al. Iodine-123-vasoactive intestinal peptide receptor scanning in patients with pancreatic cancer. J. Nucl. Med. 39, 1570-1575. 1998; Raderer, M., Kurtaran, A., Leimer, M. et al. Value of peptide receptor scintigraphy using (123)I-vasoactive intestinal peptide and (111)In-DTPA-D-Phe1-octreotide in 194 carcinoid patients: Vienna University Experience, 1993 to 1998. J. Clin. Oncol. 18, 1331-1336. 2000; Virgolini, I., Kurtaran, A., Raderer, M. et al. Vasoactive intestinal peptide receptor scintigraphy. J. Nucl. Med. 36, 1732-1739.1995).
Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP):
PACAP is a neuropeptide isolated from the ovine hypothalamus consisting of the following 38 amino acid residues containing sequence (from N- to C-terminal):
(SEQ ID No. 2)His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg- Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala- Ala-Val-Leu-Gly-Lys-Arg-Tyr-Lys-Gln-Arg-Val-Lys- Asn-Lys.
Two forms of the peptide have been identified: PACAP-38 and the C-terminally truncated PACAP-27. PACAP-27 that shares 68 percent homology with VIP has the following sequence (from N- to C-terminal):
(SEQ ID No. 3)His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg- Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala- Ala-Val-Leu
PACAP is very potent in stimulating adenylate cyclase and thus increasing adenosine 3,5-cyclic monophosphate (cAMP) in various cells. The compound functions as a hypothalamic hormone, neurotransmitter, neuromodulator, vasodilator, and neurotrophic factor. The major regulatory role of PACAP in pituitary cells appears to be the regulation of gene expression of pituitary hormones and/or regulatory proteins that control growth and differentiation of the pituitary glandular cells. These effects appear to be exhibited directly and indirectly through a paracrine or autocrine action. PACAP plays an important role in the endocrine system as a potent secretagogue for adrenaline from the adrenal medulla. The compound also stimulates the release of insulin. The stage-specific expression of PACAP in testicular germ cells during spermatogenesis suggests its regulatory role in the maturation of germ cells. In the ovary, PACAP is transiently expressed in the granulosa cells of the preovulatory follicles and appears to be involved in the LH-induced cellular events in the ovary, including prevention of follicular apoptosis. In the central nervous system, PACAP acts as a neurotransmitter or a neuromodulator. More important, PACAP is a neurotrophic factor that may play a significant role during the development of the brain. In the adult brain, PACAP appears to function as a neuroprotective factor that attenuates the neuronal damage resulting from various insults. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Two types of PACAP binding sites have been characterized. Type I binding sites exhibit a high affinity for PACAP (and a much lower affinity for VIP), whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes. These are the PACAP-specific PAC1 receptor, which is coupled to several transduction systems, and the two PACAP/VIP-indifferent VPAC1 and VPAC2 receptors, which are primarily coupled to adenylyl cyclase. PAC1 receptors are particularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testes.